Functional dissection of a molecularly identified female-specific neural pathway in mice

分子鉴定的小鼠雌性特异性神经通路的功能解剖

• 批准号: 10503353
• 负责人: Nirao Mahesh Shah
• 金额: $ 44万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503353
• 关键词: Address; Aggressive behavior; Anxiety; Behavior; Behavior Control; Behavioral; Biological; Brain; Case Study; Cell Nucleus; Clinical; Communication; Complex; Courtship; Development; Diagnosis; Disease; Dissection; Estrogen Receptor alpha; Estrogen Receptors; Female; Fiber; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Expression Profile; Genetic Transcription; Goals; Halorhodopsins; Health; Heterogeneity; Hypothalamic structure; Image; Individual; Intervention; Knowledge; Language; Lesion; Light; Link; Major Depressive Disorder; Maps; Maternal Behavior; Mental disorders; Modernization; Molecular; Mouse Strains; Mus; Nerve Degeneration; Neural Pathways; Neurodegenerative Disorders; Neurologic; Neurons; Neurosciences; Neurosecretory Systems; Output; Partner in relationship; Pathway interactions; Performance; Phenotype; Population; Progesterone Receptors; Reporter; Research; Role; Sampling; Satiation; Sex Bias; Sex Differences; Signal Transduction; Social Behavior; Social Controls; Social Interaction; Specific qualifier value; Specificity; Symptoms; Testing; Tracer; Viral; Well in self; Work; base; behavior test; cell type; deep sequencing; emotional behavior; genetic approach; insight; interest; mating behavior; neural circuit; novel; optogenetics; reduce symptoms; reproductive success; sex; sexual dimorphism; single-cell RNA sequencing; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT A central goal of modern neuroscience is to link genetically defined neural circuits with specific behaviors. Deep sequencing studies have revealed an incredible transcriptional heterogeneity of neuronal subtypes within populations previously thought to be homogeneous. Despite the discovery of such molecular heterogeneity, the functional and behavioral relevance of these recently genetically defined neuronal cell types is largely unknown. Our application addresses this gap in knowledge by focusing on the neuronal control of social behaviors. Social interactions, ranging from non-vocal communication to complex language to core behaviors such as courtship or aggression, are important for mental well-being and reproductive success. The neural circuits underpinning these diverse behaviors have been difficult to disentangle, with non-genetically targeted approaches yielding phenotypes in multiple behavioral domains. Here we propose to characterize how progesterone and estrogen receptor alpha expressing neurons (Pvl neurons) in the ventromedial hypothalamus ventrolateralis (VMHvl) regulate social behaviors. Our deep sequencing studies reveal distinct neuronal cell types within the population of Pvl neurons, with one of them restricted exclusively to females. Using newly developed Cre and Flpo mouse strains that mark this female-restricted neuronal cell type within Pvl neurons, we will determine its activity (Specific Aim 1), behavioral function (Specific Aim 2), and functional connectivity (Specific Aim 3) as these relate to female social behaviors. Together, our studies will uncover the activity dynamics, function, and connectivity of a genetically defined neuronal cell type of Pvl neurons; in parallel, we will also characterize the complementary set of remaining Pvl neurons and test their participation ins social behaviors. Thus, our research aims to understand how genetically defined cellular heterogeneity within a neuronal population relates to functional specificity in the control of social behaviors, a critical issue in neuroscience. Health Relatedness: Diverse neurodegenerative conditions and mental illnesses manifest with devastating clinical symptoms as well as a range of deficits in social and emotional behaviors. Pvl neurons within the VMHvl represent a critical hub that regulates diverse core, developmentally programmed social behaviors that differ between the sexes. Rare case reports of lesions in proximity to this region show dramatic alterations in social behaviors. Our studies therefore will provide new insights into fundamental questions in neuroscience, and they also have the potential to shed light on how dysfunction in pathways emanating from the VMHvl alters social behavior in disease states.

项目摘要/摘要 现代神经科学的一个核心目标是将基因定义的神经回路与特定行为联系起来。深的 测序研究表明，人群中神经元亚型的转录异质性令人难以置信 以前认为是同质的。尽管发现了这种分子异质性，但功能和 这些最近遗传定义的神经元细胞类型的行为相关性在很大程度上未知。我们的申请 通过关注社会行为的神经元控制来解决知识的差距。社交互动，从 与复杂语言与核心行为（例如求爱或侵略）的非声音沟通对 心理健康和生殖成功。这些不同行为的神经回路很困难 为了解开，具有非遗传靶向方法，在多个行为领域产生表型。我们在这里 提出表征孕酮和雌激素受体α在表达神经元（PVL神经元）的方式 腹侧下丘脑腹侧（VMHVL）调节社会行为。我们深入的测序研究揭示了 PVL神经元种群中的不同神经元细胞类型，其中一种仅限于女性。使用 新开发的CRE和FLPO小鼠菌株在PVL神经元内标记了这种雌性限制的神经元细胞类型，我们 将确定其活动（特定目标1），行为函数（特定目标2）和功能连接性（特定目标 3）这些与女性社会行为有关。一起，我们的研究将发现活性动态，功能和 PVL神经元的遗传定义的神经元细胞类型的连通性；同时，我们还将表征 剩余的PVL神经元的互补集并测试他们的参与社会行为。因此，我们的研究旨在 了解神经元种群中遗传定义的细胞异质性如何与功能特异性相关 在控制社会行为的过程中，神经科学中的关键问题。 健康相关性：各种神经退行性疾病和精神疾病表现出毁灭性的临床 症状以及社会和情感行为的一系列缺陷。 VMHVL内的PVL神经元代表 调节各种性别之间不同核心，开发编程的社会行为的关键枢纽。稀有的 靠近该地区病变的病例报告显示社会行为的巨大变化。因此，我们的研究将 提供有关神经科学中基本问题的新见解，它们也有可能阐明如何 VMHVL发出的途径功能障碍改变了疾病状态的社会行为。